JP-7854807-B2 - Chitosan and its uses

Inventors

• ミカエル ショーソン
• ロランス エルミッテ
• フィンセント ハーメルス
• サンドリーヌ ゴーチエ
• ピエール ドゥエット

Assignees

• キオメッド ファーマ

Dates

Publication Date

20260507

Application Date

20200520

Priority Date

20190524

Claims (20)

1. A matrix for forming an aggregated hydrogel, comprising at least one carboxyalkyl chitosan having glucosamine units, N-acetylglucosamine units, and carboxyalkyl-substituted glucosamine units, wherein the carboxyalkyl chitosan has a degree of substitution by carboxyalkyl groups ranging from 70% to 250%, expressed as the number of moles of substituents relative to the total number of moles of units; the carboxyalkyl chitosan has a degree of acetylation ranging from greater than 40% to a maximum of 80%, expressed as the number of moles of N-acetyl groups relative to the total number of moles of glucosamine units; and the carboxyalkyl chitosan is crosslinked by covalent bonds between carboxyalkyl chitosan chains.
2. The matrix according to claim 1, characterized in that the carboxyalkyl chitosan has at least 50% acetylation.
3. The matrix according to claim 1 or 2, characterized in that the carboxyalkyl chitosan is N,O-carboxyalkyl chitosan.
4. The matrix according to claim 1 or 2, characterized in that the chitosan is derived from the mycelium of an ascomycete fungus.
5. The matrix according to claim 1 or 2, characterized in that the chitosan is derived from the mycelium of the fungus Aspergillus piger.
6. The matrix according to claim 1 or 2, characterized in that the chitosan is derived from Lentinula edodes (shiitake mushroom) and/or Agaricus bisporus (white mushroom).
7. The matrix according to claim 1 or 2, characterized in that the carboxyalkyl chitosan is reacetylated.
8. The matrix according to claim 1 or 2, characterized in that the matrix is sterile.
9. The matrix according to any one of claims 1 to 8, characterized in that the matrix contains at least one hyaluronan.
10. The matrix according to any one of claims 1 to 9, characterized in that the matrix contains at least one hyaluronan obtained by fermentation.
11. The matrix according to any one of claims 1 to 10, characterized in that the matrix contains at least one hyaluronan crosslinked by covalent bonds.
12. The matrix according to any one of claims 1 to 11, characterized in that the matrix contains at least one hyaluronan co-crosslinked by covalent bonding with carboxyalkyl chitosan.
13. The matrix according to any one of claims 1 to 12, characterized in that the crosslinks are formed by a crosslinking agent that forms the covalent bonds.
14. The matrix according to claim 13, characterized in that the crosslinking agent is selected from crosslinking agents used for crosslinking polysaccharides.
15. The matrix is characterized by having antioxidant capacity by capturing free radicals, and the antioxidant capacity of each product tested herein is normalized by the formula: Normalized antioxidant capacity = TEAC (product) / TEAC (ascorbic acid 20 μg/mL), where TEAC is the Tororox equivalent antioxidant capacity, according to any one of claims 1 to 14.
16. The matrix according to claim 15, characterized in that the matrix has a normalized antioxidant capacity greater than 0.30.
17. A composition characterized by comprising at least one matrix defined according to any one of claims 1 to 16.
18. An injectable composition comprising at least one matrix as defined in any one of claims 1 to 16.
19. A pharmaceutical composition comprising at least one matrix defined according to any one of claims 1 to 16.
20. The composition according to claim 18 or 19, characterized in that it is used as an injectable, implantable, or instillable pharmaceutical composition, or as an injectable, implantable, or instillable medical device.

Description

This invention relates to cross-linked carboxyalkyl chitosan forming a matrix, compositions containing the same, methods for producing the same, and particularly to the fields of therapy, rheumatology, ophthalmology, cosmetic medicine, plastic surgery, laparotomy, dermatology, gynecology, or cosmetic medicine. Chitosan derivatives are known particularly from the patent applications and corresponding patents of Kiomeed Pharma, published under International Publication Nos. 2016/016463 and International Publication Nos. 2016/016464. Advantageous chitosan derivatives, such as carboxyalkyl chitosans, described in the patent applications and their families filed as PCT/EP2018/080763 and PCT/EP2018/080767, whose contents are incorporated by reference into this invention, are also known from Kiomeed Pharma. According to the present inventors, it would be advantageous to be able to modify the biomechanical behavior of carboxyalkyl chitosan compositions, or to increase the duration or effect of treatments provided by the presence of carboxyalkyl chitosan. However, providing such compositions with improved biomechanical properties is not obvious to those skilled in the art, especially when the preparation of hydrogels is desired. One of the technical problems with biopolymer-based compositions known to those skilled in the art, particularly among state-of-the-art hydrogels, lies in the fact that some compositions are not in the form of aggregated hydrogels. That is, hydrogels spontaneously disintegrate into distinct parts in the presence of an aqueous medium, thus forming particles, fragments. This is also known as fragmented gel or hydrogel. Such non-aggregating hydrogels are recognized as undesirable for many medical applications because they carry a risk of long-term inflammatory nodule formation or granulomatous reactions when the product is implanted in human or animal tissue (Bergerey-Galley, Aesth Surf J 24, 33, 2004). Therefore, from the perspective of the health safety of the subject or patient, it is important to avoid the formation of separate fragments and to obtain compositions in the form of aggregated hydrogels. Furthermore, for several reasons, it is sometimes desirable to avoid such aggregates in order to improve the aesthetic (visual and/or tactile) appearance of tissues that are filled with such compositions, properly biointegrated into the tissue, and allow for uniform filling. Therefore, in many applications, a cohesive hydrogel that remains in a single mass when an aqueous medium is added to it is preferred. This is also called a “homogeneous” hydrogel. Furthermore, in most applications, a hydrogel called a “smooth” hydrogel is preferred due to its visual appearance, which is lumpy or minimal. In addition to cohesiveness, the compositions according to the present invention, particularly the hydrogels, should be suitable for use in humans or animals, especially in terms of safety, immunocompatibility, bioabsorption, biomechanical properties, and duration of activity. However, not all compositions in the art exhibit such properties adequately and therefore would not conform to the present invention. Various methods are known for forming carboxylalkyl chitosans into hydrogels. In particular, Rufato et al. (Intechopen 81811, 2018), Upadhyaya et al. (J Controlled Release 2014), and Fonseca-Santos et al. (Mateur Science Engineering C 77, 1349, 2017) have identified several chitosan-based hydrogels containing carboxylalkyl chitosans for medical or pharmaceutical applications. However, none of these hydrogels meet the expectations of the inventors, particularly in terms of cohesiveness, safety, immunocompatibility, biomechanical properties, bioabsorption, and/or duration of existence or activity, and therefore do not meet the expectations of the inventors. Except for the compositions of Kiomeed Pharma described in the aforementioned patent applications PCT/EP2018/080763 and PCT/EP2018/080767, none of the carboxyalkyl chitosans used to prepare known hydrogels according to the latest technology exhibit good immunocompatibility, according to the inventors. Not all chitosans can be used to form hydrogels suitable for use in humans or animals. Currently known chitosan-based hydrogels are prepared by combining chitosan or one of its derivatives with other polymers, such as alginates, isopropylacrylamide, polyurethanes, polyacrylonitriles, gelatin, polyethylene glycol (PEG), and polyvinyl alcohol (PVA). However, these polymers are either non-biodegradable or immunoreactive and therefore do not satisfy the objectives of the present invention. For example, Huang et al. (RCS Adv 2016 D01:10.1039/C5RA26160K) prepared a hydrogel of glycol chitosan and hyaluronan, but such glycol chitosan is immunoreactive and therefore not accepted by humans. Song et al. (Sci Rep 6, 37600, 2016) prepared a hydrogel based on carboxymethyl chitosan and oxidized hyaluronan via a Schiff base reaction between the amine group of carboxym